Metastasis represents the single most significant challenge in human colorectal cancer (CRC) treatment. FasL-mediated immune surveillance by T cells is essential for the control of spontaneous cancer growth and metastasis. However, acquisition of resistance to FasL-induced apoptosis is a hallmark of human cancer, particularly metastatic human cancer. In humans, the Fas protein level is high in normal colon tissues, but is generally lower in the primary CRC, and complete loss of Fas protein is often observed in metastatic CRC. Furthermore, it has been shown that acquisition of resistance to Fas-mediated apoptosis is linked to recurrence and adverse prognosis in human CRC patients. Therefore, targeting resistance to Fas-mediated apoptosis is potentially an effective approach to overcome metastatic CRC resistance to FasL+ cytotoxic T lymphocyte (CTL) to suppress CRC immune evasion and progression. On the other hand, IRF8 plays an essential role in: 1) Fas transcription in tumor cells, 2) suppression of MDSC differentiation, and 3) regulation of CTL differentiation. Cancer is not a disease of tumor cell alone, but rather a disease of the tumor microenvironment, which consists of both tumor cells and immune cells. Therefore, systemic investigation of IRF8 functions in regulation of Fas and GM-CSF expression in tumor cells, and regulation MDSC differentiation and CTL differentiation of the immune system is of significance for understanding the cancer pathogenesis in the immune competent hosts. Our central hypothesis is that H3K9me3-mediated FAS transcriptional silencing is a molecular mechanism underlying metastatic colon carcinoma cell immune evasion and IRF8 functions in host tumor rejection through regulating MDSC and CTL differentiation. We propose to test our central hypothesis by pursuing the following 3 specific aims: 1. test the hypothesis that H3K9me3 interferes with interaction between IRF8 and the FAS promoter to represses FAS transcription in metastatic human colon carcinoma cells; 2. test the hypothesis that IRF8 represses GM-CSF expression in tumor cells to mediate tumor-induced MDSC differentiation in vivo; 3. determine the functions of IRF8 in host immune cell-mediated tumor rejection. Successful completion of these proposed studies has the potential to identify molecular targets to enhance the efficacy of CTL cancer immunotherapy to suppress metastatic colorectal cancer.